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Research ArticleArticle

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

R. Jaggi, R. S. Addison, A. R. King, B. D. Suthers and R. G. Dickinson
Drug Metabolism and Disposition February 2002, 30 (2) 161-166; DOI: https://doi.org/10.1124/dmd.30.2.161
R. Jaggi
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R. S. Addison
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A. R. King
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B. D. Suthers
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R. G. Dickinson
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Abstract

The nonsteroidal anti-inflammatory drug naproxen is primarily metabolized in humans by acyl glucuronidation to form naproxen acyl glucuronide and by O-dealkylation to form 6-O-desmethylnaproxen (DMN). DMN contains both carboxy and phenolic groups and has been shown to form acyl glucuronide and sulfate conjugates. This project aimed to investigate whether DMN formed a phenolic glucuronide and diglucuronide(s) (with both the carboxy and phenolic groups glucuronidated). Male Sprague-Dawley rats (300–350 g) with exteriorized bile flow were dosed i.v. with DMN at 50 mg/kg. Four major DMN-related peaks were detected in bile by high-performance liquid chromatography (HPLC) analysis at 225 nm, including the known acyl glucuronide and sulfate conjugates. Selective hydrolyses using acidic and alkaline conditions and digestion with β-glucuronidase allowed tentative identification of the two unknown peaks as the phenolic glucuronide of DMN and a novel acyl glucuronide-sulfate diconjugate of DMN (i.e., formed by sulfonation of the phenolic group and glucuronidation of the carboxy group). The identities were confirmed by liquid chromatography-tandem mass spectrometry analysis of individual HPLC fractions. Total recovery of the DMN dose was approximately 80%, with the sulfate conjugate (50%) and unchanged DMN (10%) being excreted predominantly in urine and the acyl glucuronide (10%), phenolic glucuronide (6%), and acyl glucuronide-sulfate diconjugate (4%) being excreted predominantly or exclusively in bile. No evidence for a diglucuronide metabolite of DMN was found in either bile or urine of the DMN-dosed rats.

Footnotes

  • This work was supported by a project grant from the National Health and Medical Research Council of Australia. Previous presentation of this work: Proceedings of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT), Annual Scientific Meeting, Newcastle, NSW, Australia, 3–6 December 2000, page 105.

  • Abbreviations used are::
    NSAID
    nonsteroidal anti-inflammatory drug
    DMN
    6-O-desmethylnaproxen
    DMN-AG
    6-O-desmethylnaproxen acyl glucuronide
    DMN-S
    6-O-desmethylnaproxen sulfate
    DMN-PG
    6-O-desmethylnaproxen phenolic glucuronide
    DMN-AG-S
    6-O-desmethylnaproxen acyl glucuronide-sulfate diconjugate
    HPLC
    high-performance liquid chromatography
    LC-MS/MS
    liquid chromatography-tandem mass spectrometry
    AUC
    area under the curve
    • Received July 31, 2001.
    • Accepted October 16, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (2)
Drug Metabolism and Disposition
Vol. 30, Issue 2
1 Feb 2002
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Research ArticleArticle

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

R. Jaggi, R. S. Addison, A. R. King, B. D. Suthers and R. G. Dickinson
Drug Metabolism and Disposition February 1, 2002, 30 (2) 161-166; DOI: https://doi.org/10.1124/dmd.30.2.161

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Research ArticleArticle

Conjugation of Desmethylnaproxen in the Rat—A Novel Acyl Glucuronide-Sulfate Diconjugate as a Major Biliary Metabolite

R. Jaggi, R. S. Addison, A. R. King, B. D. Suthers and R. G. Dickinson
Drug Metabolism and Disposition February 1, 2002, 30 (2) 161-166; DOI: https://doi.org/10.1124/dmd.30.2.161
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